1. Field of the Invention
This invention relates to the area of compositions containing synthetic conjugated estrogens and to the fields of compositions containing synthetic conjugated estrogens to be employed for replacement therapy of estrogen deficiency associated with menopausal syndrome, female hypogonadism (hypogenitalism), amenorrhea, female castration, or primary ovarian failure.
2. Description of the Prior Art
In U.S. Pat. No. 2,834,712, a process is described for preparing a mixture of conjugated estrogens from the urine of pregnant mares by absorption and extraction. The mixture consists primarily of water-soluble sulfates of a number of conjugated estrogens including estrone, 17.alpha.-estradiol, equilin, and equilenin. The mixture in the same proportion can also be duplicated essentially with synthetic estrogens. Whether synthetic or achieved from natural sources, mixtures of conjugated estrogens are applied by those skilled in the art therapeutically to relieve mental and bodily complaints occurring in the menopausal syndrome.
In relatively crude extracts containing conjugated estrogens from natural sources, natural but unknown stability constituents are apparently present, since it has been found that these products have a relatively high order of stability as compared to more highly purified estrogenic compositions, or those prepared from the synthetic conjugated estrogens. These natural conjugated estrogens are primarily derived from the urine of pregnant mares. Unfortunately, this extraction process makes the natural conjugated estrogens relatively expensive and, accordingly, they are available in limited quantities.
The pure synthetic estrogenic conjugates, while relatively inexpensive, have been found to be highly unstable, particularly in the presence of moisture. When moisture is present, even to a slight extent, as is the case with most tablets, an acid environment forms which quickly destroys the product. Obviously, the purified estrogenic conjugates are unstable when carried in aqueous media such as might be employed in injectable preparations. The instability of the estrogens is thought by those in the art to be due to hydrolysis which liberates hydrosulfuric acid and free estrogens which are for the most part inactive in the intended applications.
To combat the hydrolysis problem, it was proposed in U.S. Pat. No. 2,834,712 to add buffering agents which were capable of maintaining the pH of aqueous estrogen solutions at 6.5 to 7.5, with a preference for a slightly alkaline pH. While this approach might be satisfactory with conjugated estrogens derived from natural sources, it has been found that with synthetic estrogens, the presence of a buffer is only sufficient to provide stability for approximately six months when the estrogens are in dry tablet form. Unfortunately, it has been found that where the synthetic conjugates are present in an aqueous carrier buffered between pH 6.5 and 7.5, substantial hydrolysis has been found to occur almost immediately. A substantial need arose--the need for a synthetic conjugate which would not only be inexpensive but would retard hydrolysis and be stable for periods of time for beyond six months in order to give the corresponding pharmaceutical preparations acceptable shelf life.
The relevant prior art in the field of synthetic conjugated estrogens for use in treating menopausal syndrome, etc., was unfortunately thin. It is to be emphasized that several fields of art could be confused with the present fields at issue. In steroid chemistry, one field of art deals with the conjugated estrogens which are water-soluble, and another field deals in the chemistry of oil-soluble steroids. One field of art is concerned with conjugated estrogens used in curing vitamin deficiencies for patients with general inadequate or broadly restricted diets (for example, see MODERN DRUG ENCYCLOPEDIA AND THERAPEUTIC INDEX, (9th Edition, 1963) at 280-281; 517-521; 533; 1112-1114; 1376; 1389-1390; 1441), while another distant field of art is directed toward the use of conjugated estrogens for the replacement therapy (see Beall, U.S. Pat. No. 2,834,712) of estrogen deficiency associated with menopausal syndrome, female hypogonadism (hypogenitalism), amenorrhea, female castration, or primary ovarian failure. One art might employ salts as preservatives in non-conjugated estrogens (see MODERN DRUG, supra, at p. 1441, TRI-GENIK.TM., whereas another art might employ the same as buffers for pH control. Chemists within a particular field of art (in this instance the field of synthetic and water-soluble conjugated estrogens for use in treating menopausal syndrome, etc.) do not pay the same attention to art outside their own field for good reason--generally the chemistry is so entirely different from field of art to field of art as to render the other teachings ineffectual.
While the following art will be discussed in some detail, most of it falls outside the purview of the present invention and is deemed by Applicant to be marginally, if at all, relevant. The art was presented in the related copending application, Ser. No. 660,304, filed Feb. 23, 1976. MODERN DRUG ENCYCLOPEDIA AND THERAPEUTIC INDEX (9th Edition, 1963) at 280-281 contains a reference to CLUVISOL GERIATRIC.TM., which is a therapeutic combination of potent nutritional elements with steroids to meet the challenge of waning metabolic efficiency in old patients, with vitamin deficiencies, having a conjugated equine estrogens ("PREMARIN.TM." by Ayerst Company) and a small fraction of Vitamin E in an amount falling outside the ranges prescribed by the present invention. The Vitamin E is present for purely therapeutic purposes, not as an antioxidant, as part of a "multi-vitamin". See also PHYSICIAN'S DESK REFERENCE at 584 (1977, by Medical Economics Co., C. E. Baker, Jr., Pub.).
Also, in MODERN DRUG at 517 is listed the prescription of ESTOPHEROL TABLETS.TM. (Pitman-Moore Company) having ethinyl estradiol and Vitamin E. However, ESTOPHEROL TABLETS.TM. do not contain a conjugated estrogen, and in fact ethinyl estradiol is stable without Vitamin E in numerous oral contraceptives. In the same art as ESTOPHEROL.TM. is ESTRADURIN.TM. (Ayerst Company), employing a non-conjugated estrogen (polyestradiol phosphate) and a small amount of nicotinamide as a stabilizing element (MODERN DRUG at 518). A number of companies market various ESTROGENIC SUBSTANCES (MODERN DRUG at 518-519), none of which mention the use of stabilizers.
MODERN DRUG at 553 lists FORMATRIX.TM. (Ayerst Company) containing in each tablet 1.25 mg of conjugated estrogens ("Premarin.TM.") and a very large amount of Vitamin C (not intended as an antioxidant) for the treatment of protein depletion and ascorbic acid deficiency (see PHYSICIAN'S DESK REFERENCE, supra, at 587).
"Premarin.TM." of Ayerst Company is a preparation of orally-active, water-soluble and natural, conjugated estrogens derived from pregnant mares' urine, with no mention of any stabilizers being employed. MODERN DRUG, supra, at 1112-1114.
TESTROGYN.TM., another preparation of Ascher Company, contains estradiol and testoserone (not conjugated estrogens), with sodium bisulfate as a preservative. MODERN DRUG, supra, 1376.
THEELIN.TM. (Parke-Davis Company) is a suspension of estrogenic steroids employing suitable preservatives. MODERN DRUG, supra, at 1389-1390. TRI-GENIK.TM. (Savage Company) contains the non-conjugated estrogens estradiol, progesterone, and testosterone proprionate. A small amount of sodium meta-bisulfite is added as a preservative.
U.S. Pat. No. 2,324,348 (Anderson) teaches the use of ascorbic acid as an antioxidant in the unrelated arts of soaps and perfumes. No mention is made of employing Vitamin C in conjugated estrogens.
Louis C. Schroeter, "Sulfurous Acid Salts as Pharmaceutical Antioxidants" (50 J. PHARMACEUTICAL SCIENCES (No. 11) pp. 891 et seq. (1961) is a general article on the chemistry of the sulfurous acid salts as antioxidants. No mention is made of applying these salts to synthetic conjugated estrogens, and Schroeter never teaches any particularities of employing the salts, finding proper concentrations for applications controlling pH, etc. (See also Lachman, "Antioxidants and Chelating Agents as Stabilizers in Liquid Dosage Forms", D&Cl at pp. 36-46 (1968).
Perhaps the most pertinent reference is British Pat. No. 806,779 to Schering, which discloses a concentrated aqueous solution of estrogens and certain acids (sodium estrone sulphate, sulphurous acid and glacial acetic acid or lactic acid) adjusted to a pH of 8.0 to 8.5, with buffers present to prevent discoloration of the estrone solution for use in cosmetic preparations.
Ludwig in U.S. Pat. No. 3,666,865 (1972) seeks to stabilize trans-diethylstilbestrol (trans - "DES"), a non-conjugated estrogen, with phenolic antioxidants such as 2,4,5-trihydroxybutyrophenone, urea, and sodium carbonate. No mention is made of an alkaline antioxidant formulation with the DES. U.S. Pat. No. 3,674,869 (1972) further claims to stabilize trans-DES with sulfur-containing compounds, e.g., thiophenol or ammonium sulfide.
Beall in U.S. Pat. No. 2,884,712 seeks to control pH between a range of 6.5 to 7.5 with certain buffering mixtures such as sodium or potassium dihydrogen phosphate and sodium or potassium hydroxide, etc. No mention is made of the use of any materials as antioxidants.
A. E. Smith in 41 C.A. 7484e (1974) and in "The Instability of Oestrogens In Solution", 5 J. ENDOCRINOLOGY pp. 152 et seq (1947) describes attempts to stabilize the non-conjugated estrogens dienestrol and stilbestrol with hydroquinone. Further listed are the estrone estradiol and hexestrol in sesame oil. See MERCK INDEX (9th Edition) at 547 (1968).
D. J. Nazir et al, 56 C.A. 2743i (1962) describes the use of .alpha.-tocopherol in vegetable oils as an antioxidant to decrease peroxide values. No mention is made of employing .alpha.-tocopherol in water-soluble estrogen. H. P. Kaufmann et al, in 58 C.A. 12785h-12786a (1963) describes the efficiency of sex hormones in retarding the oxidation of buffered K linoleate. The efficiency of the hormones are admitted to be less than .alpha.-tocopherol.
N. A. Zakhorova et al, in 65 C.A. 8981h-8982a (1966) investigated the antioxidant properties of certain naturally-occurring hormones. A. G. Stren-Kovskaya in 73 C.A. 1844t-1844a (1970) estimated the amounts of selected estrogens in animal fats and oils.
In U.S. Pat. No. 3,696,195 (1972) to Crivellaio et al, there are described pharmaceutical compositions which are stabilized with thioglycerol and thioglycolic acid.
Surprisingly then, it was found in the instant case that when the synthetic conjugated estrogens were mixed in proper proportions with selected antioxidants to form a novel composition with the pH maintained at a level of not less than about 7.0, that the composition obtained was stable and prevented oxidation and hydrolysis for extremely long periods (at least two years).